Use of ribofuranose derivatives against inflammatory bowel diseases

ABSTRACT

A method for the prophylaxis or treatment of an inflammatory bowel disease is provided, comprising administering to a patient having or at risk of developing an inflammatory bowel disease a therapeutically or preventatively effective amount of one or more ribofuranose derivatives having the Formula (I):  
                 
 
wherein R is a group selected from a carboxamide, an amidine, and pharmaceutically acceptable acid addition salts thereof, and the configuration at the C 2  carbon of the ribofuranose moiety is D or L. The one or more ribofuranose derivatives (I) may be used in combination with further active agents such as antivirals or agents effective against inflammatory bowel disease.

BACKGROUND OF INVENTION

1. Field of the Invention

This invention relates to a method for treatment and prevention ofinflammatory bowel disease which comprises administering an effectiveamount of a ribofuranose derivative or a pharmaceutically acceptablesalt thereof to a mammal. This invention further relates to the use ofsuch compounds in the preparation of a medicament for the treatment andprevention of inflammatory bowel disease.

2. Background of the Invention

Inflammatory bowel disease (IBD) is a term used in the art togenerically encompass diseases of the intestine such as ulcerativecolitis (UC), irritable bowel syndrome, irritable colon syndrome andCrohn's disease (CD). For many of these diseases, in particular CD, theorigin of the disease (bacterial, viral or autoimmune) is unknown. Thereis sufficient overlap in the diagnostic criteria for UC and CD that itis sometimes impossible to say which a given patient has; however, thetype of lesion typically seen is different, as is the localization. UCmostly appears in the colon, proximal to the rectum, and thecharacteristic lesion is a superficial ulcer of the mucosa; CD canappear anywhere in the bowel, with occasional involvement of stomach,esophagus and duodenum, and the lesions are usually described asextensive linear fissures. IBD is rather common, with a prevalence thatis claimed to be in the range of 70-170 in a population of 100,000.

Crohn's disease is currently neither medically nor surgically curable,requiring approaches to treatment that maintains symptomatic control,quality of life, and minimizes short- and long-term toxicity of therapy.The current therapy of IBD usually involves the administration ofanti-inflammatory or immunosuppressive agents, such as sulfasalazine,corticosteroids, 6-mercaptopurine/azathioprine, or cyclosporine, whichusually bring only partial results. For example, IBD's such as Crohn'sdisease or ulcerative colitis have been treated in the past withsalicylic acid derivatives (such as 5aminosalicylic acid, also known as5-ASA or mesalazine; and prodrugs thereof, such as sulfasalazine).Possible side effects of 5-ASA preparations include nausea, vomiting,heartburn, diarrhea and headaches. Other treatments have been based oncorticosteroids such as cortisone, however prolonged use of steroids hasbeen known to result in side effects such as weight gain, shrinking ofthe adrenal glands, gray cataract, glaucoma, osteoporosis and diabetesmellitus. The use of immune modifying drugs such as 6-mercaptopurine andits prodrug azathioprine against Crohn's disease has increased in recentyears, but these drugs are slow acting and clinical activity cannot beexpected until several weeks or even months of treatment has elapsed. Inrecent years the use of immunomodulating monoclonal antibodies thatneutralize TNF-α has been contemplated, the only example of such anantibody that obtained marketing approval for use against Crohn'sdisease currently being infliximab. A drawback of this therapy is thehigh risk of severe infections when administered by injection and therisk of lymphoproliferative disease. A reported side effect of thetreatment with infliximab is bilateral anterior toxic optic neuropathy.

If anti-inflammatory and/or immunosuppressive therapies fail,colectomies are the last line of defense. About 30% of CD patients willneed surgery within the first year after diagnosis. In subsequent years,the rate is about 5% per year. Unfortunately, CD is characterized by ahigh rate of recurrence; about 5% of patients need a second surgery eachyear after initial surgery. In UC, a further reason for resorting tosurgery is that the patients are known to be at much increased risk fordeveloping colorectal cancer, starting 10-15 years after the diagnosisof ulcerative colitis. Presumably this is due to the recurrent cycles ofinjury to the epithelium, followed by regrowth, increasing the risk oftransformation. Accordingly, colostomy is used as prophylaxis againstthe development of cancer in UC patients.

From the above it is evident that there still exists the need of drugsand therapies that are effective against inflammatory bowel diseases andthat avoid the disadvantages of the prior art drugs and treatment.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a method for theprophylaxis or treatment of inflammatory bowel disease (IBD) comprisingadministering to a patient having or at risk of developing aninflammatory bowel disease a therapeutically or preventatively effectiveamount of one or more ribofuranose derivatives having the Formula (I):

-   -   wherein R is a group selected from a carboxamide, an amidine,        and pharmaceutically acceptable acid addition salts thereof and        the configuration at the C₂ carbon of the ribofuranose moiety is        D or L.

The method may further comprise administering a compound having Formula(I) in combination with one or more additional agents effective againstinflammatory bowel disease including, but not limited to, steroids,corticosteroids, salicylates, immunosuppressants, antibodies and/orantivirals, wherein said compound having Formula (I) and said additionalactive agent are administered simultaneously in admixture, separatelyand concomitantly, or successively.

This invention further provides the use of one or more compounds of theFormula (I) alone or in combination with one or more additional activeagents effective against inflammatory bowel disease and/or antiviralseffective against inflammatory bowel disease in the preparation of amedicament against an inflammatory bowel disease.

This invention further provides a medicament containing one or moreribofuranose derivatives having Formula (I), or a medicament containingone or more ribofuranose derivatives having Formula (I) and at least onecompound selected from the group consisting of an antiviral and afurther agent effective against inflammatory bowel disease, as acombination for the simultaneous, separate or successive administrationagainst inflammatory bowel disease.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a method for the treatmentor prophylaxis of an inflammatory bowel disease, comprisingadministering to a patient in need thereof one or more compoundsgenerally described by the Formula (I):

in a dose range effective to treat or prevent said disease, wherein R isa group selected from a carboxamide, an amidine, and pharmaceuticallyacceptable acid addition salts thereof and the configuration at the C₂carbon of the ribofuranose moiety is D or L. It is to be understood thatany derivatives of Formula (I) that perform the same function as thecompounds of Formula (I) are considered the equivalents of the Formula(I).

The numbering of the carbon atoms in the ribofuranose moiety in Formula(I) is such that the carbon bearing the triazole group is 1 (the firstcarbon atom), and the carbon atom bearing the hydroxymethyl group is 4(the fourth carbon atom). The configurations at the third and fourthcarbon atoms in the ribofuranose moiety are as in ribavirin. Theconfiguration of the C₂ carbon atom can be D or L. The configuration ofthe first carbon atom is not critical to the invention.

Another aspect of this invention is the use of a compound having Formula(I) for the preparation of a medicament against inflammatory boweldisease.

The term “inflammatory bowel disease” as used herein includes all formsof inflammatory processes in the gastrointestinal tissue, including butnot limited to, pseudomembranous colitis, hemorrhagic colitis,hemolytic-uremic syndrome colitis, collagenous colitis, ischemiccolitis, radiation colitis, drug and chemically induced colitis,diversion colitis, ulcerative colitis, irritable bowel syndrome,irritable colon syndrome and Crohn's disease; and within Crohn's diseaseall the subtypes including active, refractory, and fistulizing andCrohn's disease.

The term “against inflammatory bowel disease” as used herein refers to atherapeutic treatment or prophylaxis for inflammatory bowel disease, andan active agent “effective against inflammatory bowel disease” refers toan agent serves in the treatment or prophylaxis of inflammatory boweldisease. An “effective amount” is intended to mean that amount ofcompound that, when administered to a mammal in need of treatment orprophylaxis, is sufficient to effect treatment or prevention,respectively, of inflammatory bowel disease. The term “treating” isintended to mean at least the mitigation of inflammatory bowel diseasein a mammal, such as a human, that is affected, at least in part, by thedisease, and includes, but is not limited to, modulating and/orinhibiting the disease condition; and/or alleviating the diseasecondition. The term “prophylaxis” is intended to mean at leastpreventing the disease condition from occurring in a mammal,particularly when the mammal is found to be predisposed to having thedisease condition but has not yet been diagnosed as having it.

The terms “patient” and “subject” as used herein include any animal,including mammals and humans.

The term “medicament” as used herein includes any type of medicament fororal, nasal, topical, transdermal, rectal and parenteral administration(e.g., administration by injection), whereby the medicament can be asingle dosage containing one or more ribofuranose derivatives havingFormula (I) alone or in admixture with at least on additional agenteffective against inflammatory bowel disease, or one or moreribofuranose derivatives having Formula (I) and at least on additionalagent effective against inflammatory bowel disease in separate dosageforms. Additionally, the term “medicament” includes a kit with one ormore dosage forms containing one or more ribofuranose derivatives havingFormula (I) and separately at least one dosage form containing at leastone additional agent effective against inflammatory bowel disease, or akit with one or more dosage forms containing one or more ribofuranosederivatives having Formula (I) alone or in admixture with one or moreadditional agents effective against inflammatory bowel disease and oneor more separate dosage forms containing either the ribofuranosederivative having Formula (I) or an additional agent effective againstinflammatory bowel disease.

Examples of ribofuranose derivatives having Formula (I) used in thecompositions, medicaments, and methods according to the inventioninclude:

-   -   (1) Ribavirin        (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), which is        the compound having Formula (I) where R is (C═O)NH₂), or a        pharmaceutically acceptable acid addition salt thereof;    -   (2) Levovirin™        (1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), which is        the compound having Formula (I) where R is (C═O)NH₂), or a        pharmaceutically acceptable acid addition salt thereof. This is        the L-form of Ribavirin and its synthesis is disclosed in U.S.        Pat. No. 6,130,326, which is specifically incorporated herein by        reference;    -   (3) 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine, which is        the compound having Formula (I) where R is (C═NH)NH₂), or a        pharmaceutically acceptable acid addition salt thereof;    -   (4) 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine, which is        the compound having Formula (I) where R is (C═NH)NH₂, or a        pharmaceutically acceptable acid addition salt thereof; and    -   (5) any mixture of compounds (1)-(4).

Preferred ribofuranose derivatives having Formula (I) include1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, the hydrochloricacid addition salt of 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine(D-Viramidine®), and the hydrochloride salt of1-P-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine (L-Viramidine®). D- andL-Viramidine® are prodrugs of Ribavirin and are disclosed in U.S. Pat.No. RE 029835, which is specifically incorporated herein by reference.

The term “pharmaceutically acceptable acid addition salt” refers to acompound obtained upon treatment of a compound having Formula (I) withany pharmaceutically acceptable acid, including, but not limited to,hydrochloric, hydrobromic, acetic, propionic, p-toluenesulfonic,sulfuric, nitric or lactic acid. Methods of preparing acid additionsalts of such compounds are well known to those skilled in the art. Oneexample of such a method is described in U.S. Pat. No. 6,455,408 B1,which is incorporated herein by reference.

When an acid addition salt of the compound having Formula (I) isintended for administration by injection, the amount of acid added tothe compound having Formula (I) in the preparation of the salt may berestricted by the pH of the aqueous solution of the resulting acidaddition salt, which should be within physiologically tolerable ranges.

In certain cases, where the composition or medicament contains one ormore further agents and/or antivirals active against inflammatory boweldisease that contain an acidic hydrogen, a “pharmaceutically acceptablesalt” of the additional agents and/or antivirals may be formed bydeprotonation of the acidic hydrogen. Such deprotonation salts include,for example, the sodium or potassium salts of acyclovir and valacylovir,obtained by deprotónation of the 1-imino hydrogen. Other methods forpreparing salts of agents containing an acidic hydrogen are well knownin the art.

One embodiment of this invention comprises a method of treating orpreventing inflammatory bowel disease in a patient, comprisingadministering a therapeutically effective or preventatively effectiveamount of one or more ribofuranose derivatives having Formula (I) or theacid addition salts thereof to a patient in need thereof. The amount ofribofuranose derivative having Formula (I) that is effective for thetreatment or prevention of an inflammatory bowel disease will varydepending on the compound used and on other factors such as the bodyweight of the subject and may be determined by clinical studies onlaboratory animals or on human volunteers. An indication that atherapeutically effective in vivo amount was used is the induction of aclinical remission of the inflammatory bowel disease in question. It iswell within the ordinary skill of the art to modify the route ofadministration and dosage regimen in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

An exemplary dosage regime for a ribofuranose derivative having Formula(I) may be, when administered orally for the treatment or prophylaxis ofinflammatory bowed disease, in the range of 100 mg to 4 g per day over aperiod of 1 to 4 weeks. This dosing regime is especially suitable forthe administration of Ribavirin, and in particular for theadministration of Ribavirin for the treatment or prophylaxis of Crohn'sdisease. With the lower doses within the range of 100 mg to 1.5 g perday the treatment may be extended to up to six months, in particular forprophylactic treatment.

An exemplary dosage regime for a ribofuranose derivatives having Formula(I), when administered as injectable intravenous solution for treatmentof acute or subacute inflammatory bowel disease, is:

-   -   a) initial administration of a loading dose of about 10 to about        40 mg/kg body weight of the patient, over a period of about 20        to about 45 minutes;    -   b) administration of subsequent doses of about 5 to about 25        mg/kg body weight, in intervals of about 4 to about 6 hours, for        the first 4 days, starting one such interval after the end of        administering the loading dose of step a); and    -   c) administration of subsequent doses of about 2 mg to about 15        mg/kg body weight, in intervals of about 6 hours to about 10        hours, for the next 3 days, starting one such latter interval        after the end of the regime of step b). This dosing regime is        especially suitable for the administration of Ribavirin, and in        particular for the administration of Ribavirin for the treatment        or prophylaxis of Crohn's disease.

An exemplary dosing regime for the intravenous administration ofRibavirin according to this invention for the treatment or prophylaxisof an inflammatory bowel disease is provided in Table 1. TABLE 1 Time(hours) Day 0 18 6 12 1 Loading dose 16 mg/kg 16 mg/kg 16 mg/kg (33mg/kg) 2 16 mg/kg 16 mg/kg 16 mg/kg 16 mg/kg 3 16 mg/kg 16 mg/kg 16mg/kg 16 mg/kg 4 16 mg/kg 16 mg/kg 16 mg/kg 16 mg/kg 8 16 5  8 mg/kg  8mg/kg  8 mg/kg 6  8 mg/kg  8 mg/kg  8 mg/kg 7  8 mg/kg  8 mg/kg

In one embodiment, the compound having Formula (I) is Ribavirin. SinceRibavirin has been on the market for several years, many dosage formsand routes of administration are known, and all appropriate dosage formsand routes of administration may be utilized. For example, in additionto oral administration, ribavirin may given intravenously,intramuscularly, intraperitoneally, topically, and the like, all ofwhich are known.

A compound having Formula (I), whether alone or in the combinationtherapies or preventions as discussed herein, may be administered in anyappropriate pharmaceutical formulation, and under any appropriateprotocol. Thus, administration may take place by various routesincluding oral (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), parenteral (including subcutaneous injections,intravenous, intramuscular, by intrastemal injection or infusiontechniques), transdermal (for example as a patch which may include apenetration enhancement agent), by inhalation spray (such as in the formof a finely divided powder with an appropriate powdery diluent or aliquid aerosol, to form an ordered mixture that can be inhaled with adry powder inhaler; or as an aerosolizable solution, to be inhaled e.g.with a metered dose inhaler, for administration by insufflation (forexample as a finely divided powder), for topical use (for example ascreams, ointments, gels, or aqueous or oily solutions or suspensions),buccal and suppository administration, and other routes ofadministration, and in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose. methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices, patches, bandages, and the like.Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See, forexample, U.S. Pat. No. 5,023,252, the disclosure of which is hereinincorporated by reference. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical. Forexample, a dose of a ribofuranose derivative having Formula (I) may becombined with skin penetration enhancers, such as propylene glycol,polyethylene glycol, isopropanol, oleyl alcohol, ethoxydiglycol, sodiumxylene sulfonate, ethanol, oleic acid, N-methylpyrrolidone, laurocapram,alkanecarboxylic acids, dimethylsulfoxide, polar lipids, andN-methyl-2-pyrrolidone, and the like, which increase the permeability ofthe skin to the dose of ribofuranose derivative having Formula (I) andpermit the dose of ribofuranose derivative having Formula (I) topenetrate through the skin and into the bloodstream. A patch comprisinga ribofuranose derivative having Formula (I) may further comprise one ormore agents such as moisturizers, humectants, oils, emulsifiers,thickeners, thinners, surface active agents, fragrances, preservatives,antioxidants, vitamins, or minerals. The ribofuranose derivative havingFormula (I) may also be further combined with a polymeric substance,such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate,polyvinyl pyrrolidone, and the like, to provide the composition in gelform, which may be dissolved in solvent such as methylene chloride,evaporated to the desired viscosity, and then applied to backingmaterial to provide a patch. The backing can be any of the conventionalmaterials such as polyethylene, ethyl-vinyl acetate copolymer,polyurethane and the like.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990, which is specifically incorporated hereinby reference.

The administration of a compound having Formula (I), alone or incombination with another active ingredient as described herein, need notbe restricted to a single daily injection, but may include alternativefrequencies and routes. For example, where relatively high amounts of acompound having Formula (I) need to be delivered, two to four or moredaily injections are contemplated. Similarly, where high plasmaconcentrations of a compound having Formula (I) are desired over anextended period, a permanent delivery is contemplated. For example, amore permanent delivery may include the use of a continuous infusion, anosmotic pump, or a sustained release implant.

With respect to dosage of a compound having Formula (I), whether aloneor in combination with one or more additional agents againstinflammatory bowel disease, one of ordinary skill in the art willrecognize that a therapeutically effective amount will vary with theinfection or condition to be treated, its severity, the treatmentregimen to be employed, the pharmacokinetics of the agent used, as wellas the patient (animal or human) treated. It is further contemplatedthat while treatment success may be achieved at relatively low plasmaconcentrations of the compounds having Formula (I), other conditions mayrequire relatively high dosages.

In embodiments wherein the compound having Formula (I) is administeredtogether in admixture, separate and simultaneously or successively withone or more additional active agents and/or antivirals effective againstinflammatory disease, it is well within the skill of those of ordinaryskill in the art to decide, depending on the type of ribofuranosederivative having Formula (I) and the type of further active agentand/or antiviral to be co-administered, what type of administrationroute to choose for each compound. It is further within the skill of oneof ordinary skill in the art to determine whether the compound havingFormula (I) and the one or more additional active agents and/orantivirals a can be co-formulated into one single composition orwhether, for example due to some incompatibility, they should beformulated into separate dosage forms to then be used as a kit, oradministered independently but concomitantly or successively accordingto the respective dosing regimes. Likewise the proper choice ofexcipients and/or diluents is within the knowledge of the skilledperson, particularly as the ribofuranose derivatives having Formula (I)and the further active agents per se are known compounds that have beenpreviously used in other therapies and indications.

Because the ribofuranose derivatives having Formula (I) are watersoluble, they can be administered in the form of an injectable,especially intravenous solution in a pharmaceutically acceptablesolvent, such as water for injection (WFI) or physiological salinesolution, preferredly buffered to a pH of about 5.0 to bout 7.5, andoptionally by using suited pharmaceutically acceptable cosolvents suchas ethanol or DMSO. Conventional buffers such as phosphates,bicarbonates or citrates can be used for buffering. These solutions maybe prepared immediately prior to use.

In a further embodiment, this invention provides a method of treatmentor prophylaxis of inflammatory bowel disease in a patient comprisingadministering at least one derivative having Formula (I) in combinationwith one or more agents effective against inflammatory bowel disease.Combination therapies according to the present invention comprise theadministration of at least of compound having Formula (I) or an acidaddition salt thereof and at least one other pharmaceutically activeingredient. In this method, a compound having Formula (I) may beadministered in admixture or separately with another active agentagainst inflammatory bowel disease, and when administered separatelythis may occur simultaneously or separately in any order. The amounts ofthe active agent(s) and the compound having Formula (I) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

As stated, one embodiment of this invention for the treatment orprophylaxis of inflammatory bowel disease comprises administering one ormore derivatives having Formula (I) in an amount effective to treat orprevent the disease. Alternatively, the ribofuranose derivative havingFormula (I) can be co-administered and/or co-formulated with furtheractive agents effective against inflammatory bowel disease including,but not limited to:

-   -   (a) conventional agents used in the field of treatment of        inflammatory bowel diseases including, but not limited to,        anti-inflammatories (e.g. steroids and corticosteroids such as        cortisone and hydrocortisone, salicylates such as mesalazine and        sulfasalazine, and cytokines), immunosuppressants such as        mercaptopurine, azathioprine, metothrexate, cyclosporine and        tacrolimus, and antibodies including active fragments thereof,        such as the immunomodulating monoclonal antibody against TNF-α        known as infliximab; and/or    -   (b) further antivirals different from the ribofuranose        derivative having Formula (I) including, but not limited to,        abacavir, acyclovir, acyclovir sodium, acyclovir potassium,        adefovir, amantadine, amprenavir, atazanavir, brivudine,        capravirine, cidofovir, delavirdine, didanosine, efavirenz,        emivirin, emtricitabine, enfurvirtide, famciclovir,        fosamprenavir, foscarnet, ganciclovir, idoxuridine, indinavir,        lamivudine, lopinavir, memantine, mozenavir, nelfinavir,        nevirapine, oseltamivir, penciclovir, rimantidine, pentafuside,        ritonavir, saquinavir, stavudine, tenofovir, tipranavir,        trifluridine, valaciclovir, valganciclovir, zalcitabine,        zanamivir, zidovudin, and the pharmaceutically acceptable salts        thereof and mixtures thereof; and/or

(c) additional agents for the treatment of inflammatory bowel diseaseincluding, but not limited to, humanized monoclonal antibody againstTNF-α, flavonoids, monoclonal antibodies against IL-12 or IL-6,monoclonal antibodies against the α4β7 integrin receptor, keratinocytegrowth factor, protein inhibitors of TNF-α, glucocorticoids, peptideanalogues of glucagon-like peptide-2, glutathione peroxidase mimics,anti-sense TNF inhibitors, anti-sense ICAM-1 inhibitor, nitricoxide-releasing steroid derivatives, analogues of GLP-2, neurokinin-1antagonists, NF-kappa-B inhibitors, orally-active phosphodiesterase IVinhibitors, thiazole derivatives, 5-lipoxygenase inhibitors, L-selectinantagonists, enzyme inhibitors (e.g., tryptase inhibitors),immunosuppressive macrolides, glutathione peroxidase mimics, interferon,omega-3 fatty acids, inhibitors of cytokine synthesis,bactericidal/permeability-increasing (BPI) agents, guanyl-hydrozonecompounds, apoptotic anti-neoplastic drugs, thalidomide, and recombinantinterleukin-11. Non-limiting examples of such compounds are listed inTable 2. TABLE 2* Company Product Name Product Type/Comments AstraZenecaBudesonide Synthetic steroid Ferring Mesalazine Microsphere formulationof 5- Pharmaceuticals aminosalicylate Provalis Mesalazine pH-sensitivecoated form of 5- Procter & Gamble aminosalicylate Pharmacia OlsalazineSalicylate Shire Pharmaceuticals Balsalazide Salicylate PharmaciaMethotrexate Immunosuppressive agent Wyeth GlaxoSmithKline AzathioprineImmunoactive and immunosuppressive 6-mercaptopurine agents NovartisCyclosporin Immunosuppressive agent Schering Plough Infliximab Humanizedmonoclonal antibody against TNF-α Dong-A DA-6034 Flavonoid AbgenixABX-IL8 Monoclonal antibody against IL-12 Chugai MRA (anti-IL-6)Humanized monoclonal antibody against IL- 6 for IBD Nobex ApazaOrally-active drug targeting the lower GI tract which combinesanti-inflammatory and immunomodulatory properties Tripep TNF-Alphainhibitor Protein polymerization inhibitor that inhibits TNF-αGlaxoSmithKline SB-281832 p38 kinase inhibitor (for IBD) SB-683698Anti-inflammatory inhibitor of α4 integrin (for IBD) RepiferminKeratinocyte growth factor (for IBD) IVAX Etiprednol dicloacetateOrally-active glucocorticoid, rapidly (EPDC) converted to its inactiveform after absorption. NPS Pharmaceuticals ALX-0600 33-amino-acidpeptide analogue of glucagon-like peptide-2 (GLP-2). OXISPharmaceuticals BXT-51702 A small molecule glutathione peroxidase mimic.Accelerates metabolism of peroxides, is a potent inhibitor of NF-κB,prevents oxidative damage and downregulates the inflammatory response.ISIS Pharmaceuticals ISIS 104838 Anti-sense TNF inhibitor ISIS 2302Anti-sense ICAM-1 inhibitor (for IBD) NiCox SA NiCox 456 NO-releasingmesalazine (for IBD) NiCox 1015 NO-releasing prednisolone derivative(for IBD) Protherics CytoAb Protein inhibitor of TNF Pfizer C 96348Antagonist of neurokinin-1 (NK-1) Phytopharm plc P54 NF-kappa-Binhibitor (for IBD) Tanox Inc TNX-100 Monoclonal antibody inhibitor ofCD40 Celgene CDC-801 Lead compound from a series of small, orally-activephosphodiesterase IV inhibitors (SelCID; Selective Cytokine InhibitoryDrugs). Thalidomide TNF inhibitor Otsuka OPC-6535 Lead compound in aseries of non-peptidic, thiazole derivatives, acting as an inhibitor ofsuperoxide production by human neutrophils SangStat Corporation RDP-58Orally-active peptide inhibitor of TNFα mRNA translation. It preventstranslation of the TNF protein rather than binding to the protein toinhibit function. Cantabria AM-24 5-lipoxygenase inhibitor andL-selectin antagonist Abbott (joint D2E7 Human monoclonal antibodyagainst TNFα development with J695 Human monoclonal antibody againstIL-12 Cambridge Antibody Technology plc) Axys Pharmaceuticals APC-2059Enzyme (tryptase) inhibitor (for IBD) Fujisawa FK506 (tacrolimus)Immunosuppressive macrolide Millenium MLN-02 Humanized monoclonalantibody to the a4β7 integrin receptor (for IBD) Oxis PharmaceuticalsGPx Glutathione peroxidase mimic (in UC) Serono IFN-beta-1a Interferon(cytokine) for IBD rTBP-1 Protein inhibitor of TNF Astra ZenecaRofleponide Oral steroid with topical action (for IBD) Celltech CDP 8703^(rd) generation PEG humanized anti-TNFα antibody fragment CDP 571Fully humanized monoclonal antibody against TNFα Alizyme ATL-2502Steroid derivative in special colonic delivery formulation ElanCorporation Natalizumab Humanized monoclonal antibody against α4integrin Inkine Pharmaceuticals CBO-1011 Steroidal molecule ScheringPlough Tenovil (IL-10) Anti-inflammatory cytokine Tillotts Pharma EPAEnteric coated form of purified fish oil DHA containing free fatty acidforms of eicosapentaenoic acid (EPA) and docosahexaenoic-omega-3 acidDHA Xoma rBPI21 (Neuprex ™) A recombinant bactericidal/permeability-increasing (BPI) protein. Kills gram- negative bacteria and neutralizesthe bacterial endotoxin Cytokine Pharma CNI-1493 A syntheticguanylhydrazone compound, Sciences Inhibits the synthesis ofinflammatory cytokines such as TNF-α and IL-1 Cell Pathways CP-461 ASelective Apoptotic Antineoplastic Drug (SAAND). Induces apoptosis inneoplastic cells by inhibiting cyclic guanosine monophosphatephosphodiesterase (cGMP PDE) Wyeth-Ayerst Research rhIL-11 A recombinanthuman interleukin-11. Affects class II antigen processing and colonicepithelial cell proliferation and metabolism*Sources: Pharmaprojects, PJB Publications Ltd., status: April 2003;Target Crohn's and Colitis, Information Booklet published by theAssociation of the British Pharmaceutical Industry, status: February2002); FDA at www.clinicaltrials.gov, status: April 2003).

In any of the medicaments described herein, a compound having Formula(I) may further be co-used with infliximab, wherein the compound havingFormula (I) and infliximab can be administered together or separately.

Non-limiting examples of combinations of the ribofuranose derivativehaving Formula (I) with other active agents against inflammatory boweldisease according to this invention include the following:

-   -   (i) one or more derivatives having Formula (I) with one or more        compounds of list (a) and/or with one or more antivirals such as        those selected from list (b) and/or with one or more compounds        of list (c); and    -   (ii) a combination as described in (i), additionally with        infliximab.

Preferably, the medicaments against inflammatory bowel disease accordingto this invention may contain a combination of a ribofuranose derivativeof Formula (I) and one or more further active agents selected from anyof the above lists (a), (b) and (c). In this embodiment, theribofuranose derivative of Formula (I) and the one or more furtheractive agents are intended for simultaneous, separate or successiveadministration.

The medicaments of this invention can be formulated of any type ofadministration to a subject, including, but not limited to, intravenous,parenteral, oral, inhalation, topical, transdermal, or rectaladministration, continuous infusion, or administration with an osmoticpump or a sustained release implant.

In one preferred embodiment of a medicament of this invention, theribofuranose derivative having Formula (I) comprises at least oneribofuranose derivative selected from the group consisting of1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine,1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine, and pharmaceuticallyacceptable acid addition salts thereof such as the hydrochloric acidaddition salt of 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine and thehydrochloric acid addition salt of1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine. The medicaments of thisinvention are suitable for treating or preventing inflammatory diseasesincluding, but not limited to, pseudomembranous colitis, hemorrhagiccolitis, hemolytic-uremic syndrome colitis, collagenous colitis,ischemic colitis, radiation colitis, drug and chemically inducedcolitis, diversion colitis, ulcerative colitis, irritable bowelsyndrome, irritable colon syndrome and Crohn's disease. A preferredmedicament for the treatment of Crohn's disease comprises1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, wherein the Crohn'sdisease includes active Crohn's disease, refractory Crohn's disease, andfistulizing Crohn's disease.

One exemplary medicament of this invention comprises a ribofuranosederivative having Formula (I) in an amount between about 100 mg and 1.5grams.

Other preferred combinations and medicaments include1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide in admixture withacyclovir and 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide inadmixture with acyclovir.

In the embodiment wherein one or more agents used in the field oftreatment of inflammatory bowel diseases such as those of list (a) areco-used with one or more derivatives having Formula (I), they may beadministered in therapy and/or co-formulated in an amount or dosage fromabout the same to about half the dosage that would, when used withoutthe ribofuranose derivative having Formula (I), be effective to bringabout a reduction in the expression of proinflammatory cytokines (suchas TNF-α, TNF-β, INF-β, IL-2, IL-12) in the serum or in a tissue sampleof the intestine mucosa of the subject to be treated.

In the embodiment wherein one or more antivirals such as those of list(b) are co-used with one or more derivatives having Formula (I), theymay be administered in therapy or prevention and/or co-formulated in anamount or dosage which is from about the same to about half the dosagethat would, when used without a compound having Formula (I), beeffective, in case an ordinary viral infection, to promote an observable(e.g. by RT-PCR) reduction in virus load and/or propagation.

In the embodiment wherein one or more active agents against inflammatorybowel disease such as those of list (c) are co-used with one or morederivatives having Formula (I), they may be administered in therapyand/or be co-formulated in an amount or dosage which is from about thesame to about half the dosage that would, when used without ribofuranosederivative having Formula (I), be effective in promoting its respectivefunctional effect, which effect and corresponding assaying technique isdescribed in the respective compound's medicament information and/ordrug master file.

To prepare the pharmaceutical compositions according to the presentinvention, a therapeutically effective or prophylactically effectiveamount of one or more derivatives having Formula (I) (as well as acompound provided in list (a), (b), or (c) if co-used with the compoundhaving Formula (I)) is preferably intimately admixed with apharmaceutically acceptable carrier according to conventionalpharmaceutical compounding techniques to produce a dose. A carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral. Examples includeexcipients such as stabilizers (to promote long term storage),emulsifiers, binding agents, thickening agents, salts, preservatives,solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the ribavirin, its use in the therapeutic compositionsand preparations is contemplated. Supplementary active ingredients canalso be incorporated into the compositions and preparations as describedherein.

In preparing pharmaceutical compositions in oral dosage form, any of theusual pharmaceutical media may be used. Thus, for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives including water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like may beused. For solid oral preparations such as powders, tablets, capsules,and for solid preparations such as suppositories, suitable carriers andadditives including starches, sugar carrier, such as dextrose, mannitol,lactose and related carriers, diluents, granulating agents, lubricants,binders, disintegrating agents and the like may be used. If desired, thetablets or capsules may be enteric-coated or sustained release bystandard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater or aqueous sodium chloride solution, though other ingredientsincluding those that aid dispersion may be included. Of course, wheresterile water is to be used and maintained as sterile, the compositionsand carriers must also be sterilized. Injectable suspensions may also beprepared, in which case appropriate liquid carriers, suspending agentsand the like may be employed.

In the case of the combination therapies the ribofuranose derivativehaving Formula (I) and an additional active agent against inflammatorybowel disease such as those of lists (a), (b), and (c), the compoundhaving Formula (I) and the additional active agent may be formulated inadmixture into one single dosage. Alternatively they may be formulatedin separate dosage forms for the simultaneous, separate or sequentialuse of the two types of dosage forms and/or to be provided as amedication kit with appropriate directions of use.

The invention will now be illustrated in further detail by the followingnon-limiting examples.

EXAMPLE 1

Formulation of an injectable solution Content Ingredient (per mlsolution) Function ribavirin 100 mg agent effective against inflammatorybowel disease Na₂HPO₄ anhydr. Ph. 0.369 mg buffer Eur. KH₂PO₄ 8.718 mgbuffer 0.1 M HCl or 0.1 M q.s. adjust pH of solution to NaOH 5.4-5.6 WFIad 1 ml solvent Ph. Eur.

EXAMPLE 2 Ribavirin Assay in a DNBS (2,4 dinitrobenzenesulfonic Acid)Induced Distal Colitis in Wistar Rats as a Model for Inflammatory BowelDisease in Humans

Animals

Wistar derived female rats were provided by MDS Pharma Services TaiwanLtd. and housed in APEC^(R) cages. All animals were maintained in acontrolled temperature (22° C.-24° C.) and humidity (60-80%) environmentwith 12 hours light dark cycles for at least one week in the laboratoryprior to use. Free access to standard lab chow (LabDiet, Rodent Diet,PMI Nutrition International, USA) and tap water was granted. All aspectsof the work including housing, experimentation and disposal of animalswere performed in general accordance with the International GuidingPrinciples for Biomedical Research Involving Animals (CIOMSI PublicationNo. ISBN 9290360194, 1985).

Chemicals

DNBE (TCI, Japan), absolute ethanol (Merck, Germany), sodium chloride(Wako, Japan), sulfasalazine (Sigma, USA) and Tween 80 (Wako, Japan).

Assay

Groups of 3 Wistar derived female rats weighing 180±20 grams and fastedfor 24 hours were used. Distal colitis was induced by intra-colonicinstillation of 2,4-ninitrobenzene sulfonic acid (DNBS; 30 mg in 0.5 mLethanol 30%), which was followed by injection of air (2 mL) through acannula to ensure that the solution remained in the colon. Testsubstances (ribavirin 100 mg/kg or sulfalazine 300 mg/kg) plus vehicle(2% Tween 80 in water) were administered p.o. 24 and 2 hours before DNBSinstillation and then daily for 5 days. Two control groups weresimilarly treated with vehicle alone while challenged with either DNBS(vehicle-control) or 0.9% NaCl solution (blank-control). The animalswere sacrificed 24 hours after the final dosing of test compound andeach colon was removed and weighed. During the experiment, the presenceof diarrhea was recorded daily. Furthermore, when the abdominal cavitywas opened, adhesions between the colon and other organs were firstnoted; presence of colonic ulceration was evaluated after removal andweighing of each colon. The colon-to-body weight (BW) ratio was thencalculated for each animal according to the formula: Colon[(g)/BW(g)]×100%. The “Net” increase in the ratio ofvehicle-control+DNBS group relative to vehicle-control group was used asa base for comparison with test substance treated groups and expressedas percent decrease. A 30% or more (≧30%) reduction in colon-to-bodyweight ratio, relative to the vehicle-treated control group, isconsidered significant. The numerical data and results of the assay aregiven in Table 3. The data presented in Table 3 demonstrate thatRibavirin is effective in this IBD model. TABLE 3 B.W. Colon (g) Colonweight per Net % Treatment Dose N Day 1 Day 8 (g) 100 g B.W. IncreaseDecrease Blank-Control  10 mL/kg × 7 1 170 190 0.49 0.258 (2% Tween 80)2 170 190 0.56 0.295 3 170 190 0.51 0.268 Avg 170 190 0.52 0.274Vehicle-  10 mL/kg × 7 1 170 145 1.38 0.952 Control 2 180 155 1.09 0.703(2% Tween 80) 3 180 145 1.27 0.876 Avg 177 148 1.25 0.844 0.570Ribavirin 100 mg/kg × 7 1 180 150 1.17 0.780 2 190 155 0.96 0.619 3 180155 1.24 0.800 Avg 183 153 1.12 0.733 0.459 19 Sulfasalazine 300 mg/kg ×7 1 185 160 1.01 0.631 2 180 155 0.85 0.548 3 185 155 1.08 0.697 Avg 183157 0.98 0.625 0.351 38

Intravenous infusion solution Content (per 100 ml infusion Ingredientsolution) Function Solution 1: ribavirin 100 mg agent effective againstinflammatory bowel disease WFI ad 100 ml solvent Ph. Eur. Solution 2:acyclovir sodium 109.8 mg Further agent effective against inflammatorybowel disease WFI ad 100 ml solvent Ph. Eur. Final infusion solution:Solution 1 100 ml Solution 2 100 mlSolution 1 and 2 are mixed immediately prior to use.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A method of treatment of an inflammatory bowel disease in a subjectin need of said treatment, said method comprising: providing two or moreribofuranose derivatives having the Formula (I):

 wherein R is a group selected from the group consisting of acarboxamide, an amidine and pharmaceutically acceptable acid additionsalts thereof and the configuration at the C₂ carbon of the ribofuranosemoiety is D in at least one of the ribofuranose derivatives and theconfiguration at the C₂ carbon of the ribofuranose moiety is L in atleast another one of the ribofuranose derivatives; and administeringsaid two or more ribofuranose derivatives to said subject in an amounteffective to treat said inflammatory bowel disease.
 2. The method ofclaim 1, wherein the ribofuranose derivatives having the Formula (I)comprise at least one derivative selected from the group consisting of1-B-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine,1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine, pharmaceuticallyacceptable acid addition salts thereof.
 3. The method of claim 2,wherein the ribofuranose derivatives having Formula (I) comprise1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
 4. The method ofclaim 2, wherein the ribofuranose derivatives having Formula (I)comprise 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
 5. Themethod of claim 2, wherein the ribofuranose derivatives having Formula(I) comprise 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine.
 6. Themethod of claim 2, wherein the ribofuranose derivatives having Formula(I) comprise 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine.
 7. Themethod of claim 2, wherein the ribofuranose derivatives comprise thehydrochloric acid addition salt of1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-amidine.
 8. The method of claim2, wherein the ribofuranose derivatives comprise the hydrochloric acidaddition salt of 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-amidine.
 9. Themethod of claim 1, wherein the ribofuranose derivatives having Formula(I) comprise 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and theinflammatory bowel disease is Crohn's disease.
 10. The method of claim9, wherein said Crohn's disease is selected from the group consisting ofactive Crohn's disease, refractory Crohn's disease, and fistulizingCrohn's disease.
 11. The method of claim 1, wherein the ribofuranosederivatives having Formula (I) are provided in combination with anantiviral, wherein the ribofuranose derivatives having Formula (I) andthe antiviral are administered to said subject simultaneously as anadmixture, separately and simultaneously, or separately in any order.12. The method of claim 11, wherein said antiviral agent is selectedfrom the group consisting of abacavir, acyclovir, acyclovir sodium,acyclovir potassium, adefovir, amantadine, amprenavir, atazanavir,brivudine, capravirine, cidofovir, delavirdine, didanosine, efavirenz,emivirin, emtricitabine, enfurvirtide, famciclovir, fosamprenavir,foscarnet, ganciclovir, idoxuridine, indinavir, lamivudine, lopinavir,memantine, mozenavir, nelfinavir, nevirapine, oseltamivir, penciclovir,rimantidine, pentafuside, ritonavir, saquinavir, stavudine, tenofovir,tipranavir, trifluridine, valaciclovir, valganciclovir, zalcitabine,zanamivir, zidovudin, and the pharmaceutically acceptable salts thereofand mixtures thereof.
 13. The method of claim 11, wherein theribofuranose derivatives are1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the antiviral isacyclovir.
 14. The method of claim 1 or 11 further comprising providingone or more further agents effective against an inflammatory boweldisease for simultaneous or successive administration with saidderivatives having Formula (I), wherein said further active agent isselected from the group consisting of anti-inflammatories,immunosuppressants, antibodies, antibody fragments, humanized monoclonalantibody against TNF-α, flavonoids, monoclonal antibodies against IL-12,monoclonal antibodies against IL-6, monoclonal antibodies against theα4β7 integrin receptor, keratinocyte growth factor, protein inhibitorsof TNF-α, glucocorticoids, peptide analogues of glucagon-like peptide-2,glutathione peroxidase mimics, anti-sense TNF inhibitors, anti-senseICAM-1 inhibitor, nitric oxide-releasing steroid derivatives, analoguesof GLP-2, neurokinin-1 antagonists, NF-kappa-B inhibitors, orally-activephosphodiesterase IV inhibitors, thiazole derivatives, 5-lipoxygenaseinhibitors, L-selectin antagonists, enzyme inhibitors, tryptaseinhibitors, immunosuppressive macrolides, monoclonal antibodies againstthe α4β7 integrin receptor, glutathione peroxidase mimics, interferon,omega-3 fatty acids, inhibitors of cytokine synthesis,bactericidal/permeability agents, guanyl-hydrozone compounds, apoptoticantineoplastic drugs, thalidomide, recombinant interleukin-11 andmixtures thereof.
 15. The method of claim 1, 11 or 14 further comprisingproviding inflixamab, wherein the ribofuranose derivatives havingFormula (I) and infliximab are administered to said subject as anadmixture, separately and simultaneously, or separately in any order.16. The method of claim 1, wherein said administration comprisesparenteral administration, oral administration, inhalation, topicaladministration, transdermal administration, rectal administration,continuous infusion, or administration with an osmotic pump or asustained release implant.
 17. The method of claim 1, wherein said stepof administering comprises orally administering the ribofuranosederivatives having Formula (I) in a dose between 100 mg and 1.5 g perday for one to four weeks.
 18. The method of claim 17, wherein theribofuranose derivatives having Formula (I) comprise1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the inflammatorybowel disease is Crohn's disease.
 19. The method of claim 1, wherein thestep of administering comprises: (a) intravenously administering theribofuranose derivatives having Formula (I) in a dose of about 10 to 40mg/kg of body weight of the patient for about 20 to 45 minutes; (b)intravenously administering the ribofuranose derivatives having Formula(I) in a dose of about 5 to 25 mg/kg of body weight of the patient everysix hours for four days; and (c) intravenously administering theribofuranose derivatives having Formula (I) in a dose of about 2 to 15mg/kg of body weight of the patient every six to eight hours for threedays.
 20. The method of claim 19, wherein the ribofuranose derivativeshaving Formula (I) comprise1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the inflammatorybowel disease is Crohn's disease.
 21. The method of claim 19, whereinthe step of administering comprises: (a) intravenously administering theribofuranose derivatives having Formula (I) in a dose of 33 mg/kg ofbody weight of the patient for 30 minutes; (b) intravenouslyadministering the ribofuranose derivatives having Formula (I) in a doseof 16 mg/kg of body weight of the patient every six hours for four days;and (c) intravenously administering the ribofuranose derivatives havingFormula (I) in a dose of 8 mg/kg of body weight of the patient everyeight hours for three days.
 22. The method of claim 21, wherein theribofuranose derivatives having Formula (I) comprise1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and the inflammatorybowel disease is Crohn's disease.
 23. The method of claim 1, wherein thedisease is selected from the group consisting of pseudomembranouscolitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis,collagenous colitis, ischemic colitis, radiation colitis, drug andchemically induced colitis, diversion colitis, ulcerative colitis,irritable bowel syndrome, irritable colon syndrome and Crohn's disease.24. The method of claim 1, wherein the subject is a human.
 25. Themethod of claim 10, wherein the agent is administered in an amount thatis from about half the dosage to the same dosage which is, whenadministered alone, effective to treat said inflammatory bowel disease.26-63. (canceled)